Abstract: Advanced processes for peroxymonosulfate (PMS)-based oxidation are efficient in eliminating toxic and refractory organic pollutants from sewage. The activation of electron-withdrawing \mathrmHSO_5^- releases reactive species, including sulfate radical ( \text·\mathrmS\mathrmO_4^- ), hydroxyl radical ( \text·\mathrmO\mathrmH ), superoxide radical ( \text·\mathrmO_2^- ), and singlet oxygen (¹O₂), which can induce the degradation of organic contaminants. In this work, we synthesized a variety of M-OMS-2 nanorods (M = Co, Ni, Cu, Fe) by doping Co²⁺, Ni²⁺, Cu²⁺, or Fe³⁺ into manganese oxide octahedral molecular sieve (OMS-2) to efficiently remove sulfamethoxazole (SMX) via PMS activation. The catalytic performance of M-OMS-2 in SMX elimination via PMS activation was assessed. The nanorods obtained in decreasing order of SMX removal rate were Cu-OMS-2 (96.40%), Co-OMS-2 (88.00%), Ni-OMS-2 (87.20%), Fe-OMS-2 (35.00%), and OMS-2 (33.50%). Then, the kinetics and structure–activity relationship of the M-OMS-2 nanorods during the elimination of SMX were investigated. The feasible mechanism underlying SMX degradation by the Cu-OMS-2/PMS system was further investigated with a quenching experiment, high-resolution mass spectroscopy, and electron paramagnetic resonance. Results showed that SMX degradation efficiency was enhanced in seawater and tap water, demonstrating the potential application of Cu-OMS-2/PMS system in sewage treatment.